Huntington's disease (HD) is a dominant hereditary disease that is caused by the expansion of a CAG triplet repeat encoding a stretch of polyglutamine (polyQ) within Huntingtin (Htt), the protein product of the HD gene. The expansion of the Htt polyQ stretch confers a deleterious gain-of-function while simultaneous loss of normal Htt function can also contribute to pathogenesis. In HD and other adult onset neurodegenerative diseases, evidence is accumulating suggesting that dysfunction during development can contribute to later pathogenesis. Alternatively, compensatory mechanisms acting during development can delay the onset of neurodegeneration and motor/behavioral symptoms. Our overall objective is to use novel repressible/inducible knockin mouse models for HD to explore the role of developmental expression and compensation in the progression of Huntington's disease, and to determine if there are critical times during development or at different ages in the adult, when normal htt expression must be maintained. To this end, we are developing knockin mouse models that express either normal (7Q) or mutant (140Q) versions of the mouse HD gene (Hdh) that have lactose operator (LacO) sequences inserted within their promoters. When these HdhLacO alleles are expressed together with a transgene encoding a version of the bacterial lactose repressor (LacIR) that functions in mice (HdhLacO-3xFLAG-7Q/-;-actin LacIR-tg and HdhLacO-140Q/+;-actin LacIR-tg mice, respectively), wild-type or mutant htt expression can be turned-on or turned-off by administering or withdrawing isopropyl - D thiogalactoside (IPTG, a lactose analog) in the mouse's drinking water. In Aim 1, we propose to study the consequences of developmentally-restricted mutant htt expression on adult behavioral and neuropathological phenotypes by turning-on the expression of mutant htt at conception, and turning-off mutant htt expression at 1 month of age in HdhLacO-140Q/+;-actin LacIR-tg mice. Similarly, we will turn-on mutant htt expression at one month of age to study the role of compensation in HD pathogenesis. In Aim 2, we propose to determine if there are critical periods during the life of the mouse when normal htt expression must be maintained by turning-off normal htt expression at different ages in HdhLacO-3xFLAG-7Q/-;-actin LacIR-tg mice. Moreover, to model the therapeutic efficacy and safety of reducing overall Htt expression (Aim 3), we will combine both LacO-modified Hdh alleles in one mouse model (HdhLacO-140Q/LacO-3xFLAG-7Q;-actin LacIR-tg mice), and suppress both normal and mutant htt expression at 6 months or 1 year of age. PUBLIC HEALTH RELEVANCE: The development and application of new mouse models for Huntington's disease (HD) that can reversible turn-on or turn-off mutant and normal HD gene expression will enable us to explore developmental and compensatory mechanisms in HD pathogenesis, and will allow us to evaluate the efficacy and safety of potential therapeutic strategies for HD that are based on suppressing HD gene expression.